We show that subwavelength diffracted wave fields may be managed inside multilayered plasmonic devices to achieve ultra-resolving lensing. For that purpose we first transform both homogeneous waves ...and a broad band of evanescent waves into propagating Bloch modes by means of a metal/dielectric (MD) superlattice. Beam spreading is subsequently compensated by means of negative refraction in a plasmon-induced anisotropic medium that is cemented behind. A precise design of the superlens doublet may lead to nearly aberration-free images with subwavelength resolution in spite of using optical paths longer than a wavelength.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The ability of G protein-coupled receptors (GPCRs) to form homo- and heteromeric complexes has important implications for the regulation of cellular events. A notable example of heteromer formation ...is the interaction of the calcitonin receptor-like receptor (CRLR) with different members of the receptor activity modifying protein (RAMP) family, which results in the formation of two different receptors, a calcitonin gene-related peptide (CGRP) receptor and an adrenomedullin receptor. To analyze the role of RAMPs in determining ligand specificity, we have co-expressed CRLR and RAMP proteins in the yeast Saccharomyces cerevisiae, which provides a null system to study the function of mammalian receptors. Co-expression of RAMP1 and CRLR reconstituted a CGRP receptor that was able to activate the pheromone-signaling pathway with pharmacological properties similar to those observed previously in mammalian cells. Co-expression of CRLR with RAMP2 or RAMP3 resulted in a response with the pharmacological properties of an adrenomedullin receptor. These data indicate that RAMPs are necessary and sufficient to determine ligand specificity of CRLR. Contrary to observations in mammalian cells, the glycosylation of CRLR was not affected by the presence of RAMPs in yeast, indicating that glycosylation of CRLR is not the prime determinant of ligand specificity. The first functional reconstitution of a heteromeric seven transmembrane receptor in yeast suggests this organism as a useful research tool to study the molecular nature of other heteromeric receptors.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
To obtain an accurate algorithm for calculating the keratometric index that minimizes the errors in the calculation of corneal power assuming only a single corneal surface in the range of corneal ...curvatures of the normal population.
Corneal power was calculated by using the classical keratometric index and also by using the Gaussian equation. Differences between types of calculation of corneal power were determined and modeled by regression analysis.
We proposed two options for the selection of the most appropriate keratometric index (n(k)) value for each specific case. First was the use of specific linear equations (depending on the ratio of the anterior to the posterior curvature, k ratio) according to the value of the central radius of curvature of the anterior corneal surface (r(1c)) in 0.1 mm steps and the theoretical eye model considered. The second was the use of a general simplified equation only requiring r(1c) (Gullstrand eye model, n(k) = -0.0064286r(1c) + 1.37688; Le Grand eye model, n(k) = -0.0063804r(1c) + 1.37806).
The generalization of the keratometric index (n(k)) value is not an appropriate approximation for the estimation of the corneal power and it can lead to significant errors. We proposed a new algorithm depending on r(1c), with a maximal associated error in the calculation of the corneal power of 0.5 D and without requiring knowledge of the posterior corneal curvature.
Objective To analyze differences in the variables associated with severity of suicidal intent and in the main factors associated with intent when comparing younger and older adults. Design ...Observational, descriptive cross-sectional study. Setting Four general hospitals in Madrid, Spain. Participants Eight hundred seventy suicide attempts by 793 subjects split into two groups: 18–54 year olds and subjects older than 55 years. Measurements The authors tested the factorial latent structure of suicidal intent through multigroup confirmatory factor analysis for categorical outcomes and performed statistical tests of invariance across age groups using the DIFFTEST procedure. Then, they tested a multiple indicators-multiple causes (MIMIC) model including different covariates regressed on the latent factor “intent” and performed two separate MIMIC models for younger and older adults to test for differential patterns. Results Older adults had higher suicidal intent than younger adults ( z = 2.63, p = 0.009). The final model for the whole sample showed a relationship of intent with previous attempts, support, mood disorder, personality disorder, substance-related disorder, and schizophrenia and other psychotic disorders. The model showed an adequate fit (χ212 = 22.23, p = 0.035; comparative fit index = 0.986; Tucker-Lewis index = 0.980; root mean square error of approximation = 0.031; weighted root mean square residual = 0.727). All covariates had significant weights in the younger group, but in the older group, only previous attempts and mood disorders were significantly related to intent severity. Conclusions The pattern of variables associated with suicidal intent varies with age. Recognition, and treatment of geriatric depression may be the most effective measure to prevent suicidal behavior in older adults.
A nonsingular, polarization-dependent, 3D impulse response is derived to determine unambiguously the amplitude distribution in the image volume of a negative-refractive-index layered lens. The ...generalized amplitude transfer function is introduced to gain a deep insight into the resolution power of the optical element. In the near-field regime, fine details containing some depth information may be transmitted through the lens. Metamaterials with moderate absorption are appropriate for subwavelength resolution keeping a limited degree of depth discrimination.
Full text
Available for:
DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
We investigated the diffraction behavior of plasmonic Bessel beams propagating in metal-dielectric stratified materials and wire media. Our results reveal various regimes in which polarization ...singularities are selectively maintained. This polarization-pass effect can be controlled by appropriately setting the filling factor of the metallic inclusions and its internal periodic distribution. These results may have implications in the development of devices at the nanoscale level for manipulation of polarization and angular momentum of cylindrical vector beams.
Abstract
The clinical successes achieved by different immunotherapies have resulted in a paradigm shift in treatment modalities. Despite these significant advances, not all patients benefit from the ...use of these therapies, creating a need to develop additional approaches to enhance and broaden their clinical application. To identify genes whose products can increase or decrease the sensitivity of tumor cells to the immune system, we used a CTL assay to screen a whole genomic CRISPR library. We co-culture a mouse cell line, ID8, expressing a model antigen (Ova) with transgenic CD8 T cells (OT-I) recognizing this antigen. A set of controls that enhance or decrease CTL activity behaved as expected. Comparison of the CRISPR score identified several hits that increased or decreased the sensitivity of the tumor cells to CTL killing. Subsets of these hits belong to two pathways involved in CTL-mediated killing: the IFN-γ and the TNF-α signaling pathways. We evaluated which of these hits would be amenable to therapeutic modulation, and decided to focus on the kinase TAK1 for confirmation and validation studies. A TAK1 deficient cell line was more sensitive to CTL killing, which was prevented by expression of TAK1, confirming the role of TAK1 in this process. A TAK1 gene carrying an inactivation mutation K63W did not rescue the effects of TAK1 KO, indicating that TAK1 enzymatic activity was necessary. Several pathways mediate CTL killing: Perforin/Granzyme B, IFN-γ, TNF-α, Fas & TRAIL pathways. To determine TAK1 MOA, we studied the effects of a Perforin/Granzyme B inhibitor CMA. CMA inhibited CTL activity in a dose-dependent manner on WT cells, but did not inhibit CTL activity on TAK1 deficient cells, indicating TAK1 effects are independent of this pathway. We then tested the sensitivity of TAK1 KO cells to TNF-α. TAK1 KO cells were more sensitive to TNF-α mediated killing, and similar results were observed with several additional cell lines (MC38, EMT6, KP). TNF-α can activate the JNK, p38, and NF-κB pathways, and the apoptosis extrinsic pathway to regulate cell growth and cell death. Kinetics studies monitoring pathway activity upon TNF-α stimulation showed that TAK1 KO cell lines induced cFLIP degradation before observing PARP cleavage, and that the NF-κB pathway, which has been observed to mediate cFLIP synthesis, was not activated. We proceeded to evaluate the effects of TAK1 deficiency in a mouse syngeneic model. TAK1 deficiency resulted in reduced growth and increased survival in the MC38 in vivo model. In summary, by screening a CRISPR library against a CTL assay, we identified TAK1 as a novel potential target for immunotherapies. TAK1 deficiency enhances CTL killing and results in decreased tumor growth and increased survival in vivo. This results support the development of TAK1 inhibitors to enhance the anti-tumor action of the immune system.
Citation Format: Juan J. Miret, Troy A. Luster, Patrick Lizotte, Min Wu, Sarah Nzikoba, Luke Taus J. Taus, Prafulla C. Gokhale, Paul Kirschmeier, David Barbie, Cloud P. Paweletz. TAK1 deficiency in tumor cells enhances sensitivity to CTL-mediated killing via TNF-α abstract. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5543.
PDF
